SUMMARY Heartfailure(HF)isaleadingcauseofdeathworldwide,andtheleadingcauseofhospitaladmissionsinpatients over65intheUS.Thefive-yearmortalityrateforpatientswithHFremains~50%.Neurohormonalblockadehas beenthemainstayofHFmanagementfordecades,butthelimitsofitsbenefitshavelikelybeenreached.Novel therapies, addressing novel pathways, are direly needed. Mounting evidence indicates that the failing heart is an ?engineout of fuel? that fails tousefuel appropriatelyto satisfy its metabolic demands. Understanding how thehearthandlesvariousfuelsduringhealthanddisease,andfindingwaystomodulatethesepathways,thus holds great promise as novel therapies, orthologous to current neurohormonal blockade. We focus here on branchedchainaminoacids(BCAAs).PlasmaBCAAlevelshavebeennotedfordecadestobeelevatedinheart failure,andoftentopredictadverseoutcomes.TheexpressionofBCAAcatabolicgenesisthemostsignificantly suppressedsignatureinhumanfailinghearts.Despitetheseobservations,however,theroleofBCAAsinheart failure remains poorly understood, and the therapeutic opportunities consequently remain ill-defined. For example,theextenttowhichBCAAconsumptionbytheheartisrequiredfornormalorinjuredcardiacfunction isunknown.SimilarlyunknownistheroleofBCAAcatabolisminothertissues,inparticulartheskeletalmuscle, which we have shown carries out the lion?s share of BCAA catabolism in the whole organism. Finally, comprehensive quantification of BCAA (and other metabolite) consumption in human hearts, in situ, in both failing and nonfailing conditions, has never been done. To address these questions, we will use here novel genetic murine models;? murine models of various types of heart failure;? and investigations with human cells, tissue,andplasma,toinvestigateindepththeroleofBCAAsinheartfailure.Thesehighlyfocusedstudieswill elucidatetheroleofBCAAcatabolismincardiacfunction,withastrongfocusonhumanstudies.